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Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants

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Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. / Rajatileka, Shavanthi; Odd, David; Robinson, Matthew T.; Spittle, Alexandra C.; Dwomoh, Louis; Williams, Maggie; Harding, David; Wagstaff, Miles; Owen, Marie; Crosby, Charlene; Ching, Jared; Molnár, Elek; Luyt, Karen; Váradi, Anikó.

In: Molecular Neurobiology, Vol. 55, 03.2018, p. 2013-2024.

Research output: Contribution to journalArticle

Harvard

Rajatileka, S, Odd, D, Robinson, MT, Spittle, AC, Dwomoh, L, Williams, M, Harding, D, Wagstaff, M, Owen, M, Crosby, C, Ching, J, Molnár, E, Luyt, K & Váradi, A 2018, 'Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants', Molecular Neurobiology, vol. 55, pp. 2013-2024. https://doi.org/10.1007/s12035-017-0462-1

APA

Rajatileka, S., Odd, D., Robinson, M. T., Spittle, A. C., Dwomoh, L., Williams, M., ... Váradi, A. (2018). Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. Molecular Neurobiology, 55, 2013-2024. https://doi.org/10.1007/s12035-017-0462-1

Vancouver

Rajatileka S, Odd D, Robinson MT, Spittle AC, Dwomoh L, Williams M et al. Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. Molecular Neurobiology. 2018 Mar;55:2013-2024. https://doi.org/10.1007/s12035-017-0462-1

Author

Rajatileka, Shavanthi ; Odd, David ; Robinson, Matthew T. ; Spittle, Alexandra C. ; Dwomoh, Louis ; Williams, Maggie ; Harding, David ; Wagstaff, Miles ; Owen, Marie ; Crosby, Charlene ; Ching, Jared ; Molnár, Elek ; Luyt, Karen ; Váradi, Anikó. / Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. In: Molecular Neurobiology. 2018 ; Vol. 55. pp. 2013-2024.

Bibtex

@article{33e62452769647e5a5c567a03df9469f,
title = "Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants",
abstract = "Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4{\%} of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6{\%} of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies.",
keywords = "Brain injury, Cerebral palsy, Excitatory amino acid transporter 2 (EAAT2), Glutamate, Glutamate transporter, Neurodevelopmental disorder, Periventricular leukomalacia, Preterm infant, Promoter activity, Pyrosequencing, Single nucleotide polymorphism",
author = "Shavanthi Rajatileka and David Odd and Robinson, {Matthew T.} and Spittle, {Alexandra C.} and Louis Dwomoh and Maggie Williams and David Harding and Miles Wagstaff and Marie Owen and Charlene Crosby and Jared Ching and Elek Moln{\'a}r and Karen Luyt and Anik{\'o} V{\'a}radi",
note = "16-Feb-17",
year = "2018",
month = "3",
doi = "10.1007/s12035-017-0462-1",
language = "English",
volume = "55",
pages = "2013--2024",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants

AU - Rajatileka, Shavanthi

AU - Odd, David

AU - Robinson, Matthew T.

AU - Spittle, Alexandra C.

AU - Dwomoh, Louis

AU - Williams, Maggie

AU - Harding, David

AU - Wagstaff, Miles

AU - Owen, Marie

AU - Crosby, Charlene

AU - Ching, Jared

AU - Molnár, Elek

AU - Luyt, Karen

AU - Váradi, Anikó

N1 - 16-Feb-17

PY - 2018/3

Y1 - 2018/3

N2 - Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies.

AB - Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies.

KW - Brain injury

KW - Cerebral palsy

KW - Excitatory amino acid transporter 2 (EAAT2)

KW - Glutamate

KW - Glutamate transporter

KW - Neurodevelopmental disorder

KW - Periventricular leukomalacia

KW - Preterm infant

KW - Promoter activity

KW - Pyrosequencing

KW - Single nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85014561372&partnerID=8YFLogxK

U2 - 10.1007/s12035-017-0462-1

DO - 10.1007/s12035-017-0462-1

M3 - Article

VL - 55

SP - 2013

EP - 2024

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

ER -